Neuraxial anaesthesia is frequently used for lower limb arthroplasty but it is unclear whether benefits vary among patients receiving different subtypes of neuraxial anaesthesia. We evaluated whether ...differences in risk for adverse postoperative outcomes exist between patients receiving combined spinal and epidural (CSE), epidural, or spinal anaesthesia.
In this retrospective cohort study, we identified 40 852 patients who underwent total hip and knee arthroplasty (THA and TKA) procedures under neuraxial anaesthesia (34 301 CSE, 2464 epidural, 4087 spinal) between 2005 and 2014 at a single institution. We used multivariable logistic regression to evaluate the following outcomes: cardiac, pulmonary, gastrointestinal, renal/genitourinary, and thromboembolic complications, and prolonged length of stay.
Compared with CSE, spinal anaesthesia was associated with reduced adjusted odds for cardiac odds ratio (OR), 0.68; 95% confidence interval (CI), 0.52–0.89, pulmonary (OR: 0.51; 95% CI: 0.38–0.68), gastrointestinal (OR: 0.50; 95% CI: 0.32–0.78), and thromboembolic complications (OR: 0.40; 95% CI: 0.23–0.73), and prolonged length of stay (OR: 0.72; 95% CI: 0.66–0.80). Patients who received epidural anaesthesia did not have significantly different odds for any outcomes compared with CSE patients.
We identified clear differences in risk for certain postoperative events by subtype of neuraxial anaesthesia, suggesting that spinal anaesthesia is associated with the most favourable outcomes profile.
We used cDNA microarrays to assess gene expression profiles in 60 human cancer cell lines used in a drug discovery screen by the National Cancer Institute. Using these data, we linked bioinformatics ...and chemoinformatics by correlating gene expression and drug activity patterns in the NCI60 lines. Clustering the cell lines on the basis of gene expression yielded relationships very different from those obtained by clustering the cell lines on the basis of their response to drugs. Gene-drug relationships for the clinical agents 5-fluorouracil and L-asparaginase exemplify how variations in the transcript levels of particular genes relate to mechanisms of drug sensitivity and resistance. This is the first study to integrate large databases on gene expression and molecular pharmacology.
Advances in genomics, proteomics and molecular pathology have generated many candidate biomarkers with potential clinical value. Their use for cancer staging and personalization of therapy at the ...time of diagnosis could improve patient care. However, translation from bench to bedside outside of the research setting has proved more difficult than might have been expected. Understanding how and when biomarkers can be integrated into clinical care is crucial if we want to translate the promise into reality.
In an effort to develop a genomics-based approach to the prediction of drug response, we have developed an algorithm for classification of cell line chemosensitivity based on gene expression profiles ...alone. Using oligonucleotide microarrays, the expression levels of 6,817 genes were measured in a panel of 60 human cancer cell lines (the NCI-60) for which the chemosensitivity profiles of thousands of chemical compounds have been determined. We sought to determine whether the gene expression signatures of untreated cells were sufficient for the prediction of chemosensitivity. Gene expression-based classifiers of sensitivity or resistance for 232 compounds were generated and then evaluated on independent sets of data. The classifiers were designed to be independent of the cells' tissue of origin. The accuracy of chemosensitivity prediction was considerably better than would be expected by chance. Eighty-eight of 232 expression-based classifiers performed accurately (with P < 0.05) on an independent test set, whereas only 12 of the 232 would be expected to do so by chance. These results suggest that at least for a subset of compounds genomic approaches to chemosensitivity prediction are feasible.
This study was designed to examine the behaviorial immunohistochemical changes of spinal glial cells and spinal Interleukin (IL)-1beta expression after various nerve root injuries used as models of ...lumbar radiculopathy.
In order to better understand the role of central inflammation in the pathophysiologic mechanisms that give rise to pain associated with lumbar radiculopathy, this research studied the relationship between pain-related behavior associated with spinal glial activation and IL-1beta expression generated by three types of nerve root injury: loose ligation with chromic gut, loose ligation with silk, and tight ligation with silk.
An animal model of lumbar radiculopathy originally described by Kawakami and Weinstein involved loose ligation of unilateral L4-L6 nerve roots with chromic gut. Characterization and establishment of such an animal model of low back pain enables further investigation of the nature of the pathophysiologic mechanisms associated with lumbar radiculopathy in humans.
Seventy-three rats were divided into four treatment groups. Chromic group (n = 25): The L5 nerve roots (dorsal and ventral) were exposed by hemilaminectomy and loosely ligated with chromic gut. Tight silk group (n = 18): The exposed L5 nerve roots were tightly ligated extradurally with 5-0 silk suture. Loose silk group (n = 15): two loose ligatures of 5-0 silk were placed around the exposed L5 nerve roots. Sham group (n = 15): the rats were subjected to laminectomy alone for exposing nerve roots. Following surgery, thermal hyperalgesia and mechanical allodynia was assessed time-dependently up to 42 days post operatively. At 1, 3, 7, 14, and 42 days postoperatively, the rats in each group were perfused with fixative. The L5 spinal cord segments was harvested and cryosectioned for glial and cytokine immunohistochemistry.
In the chromic and the tight silk group, an immediate and sustained mechanical allodynia was observed in the ipsilateral hind paw up to 35 days postoperatively. The loose silk group also showed an immediate mechanical allodynia that subsided by 14 days postoperatively. Sham-treated animals exhibited mild mechanicalallodynia for the initial 7 days after the surgery. Thermalhyperalgesia was evident in the three primary treatment groups, but not in the sham-treated rats. OX-42 expression was elevated in the gray matter of the L5 spinal section by 3 days in the chromic, the tight silk, and the loose silk groups as compared to the sham group. Astrocytic activation increased over time in all groups except the sham group. There was no direct correlation between degree of microglial response and severity of pain behaviors. In contrast, astrocytic activation demonstrated a direct relationship with the elevation of mechanical allodynia for the first 7 days. In addition, spinal IL-1beta protein expression was increased bilaterally in the superficial layer of the dorsal horn and cell nuclei of the ventral horns in the ligature treated groups as compared with the sham group.
Direct mechanical and/or chemical injury to lumbar roots in the rat gives rise to pain behavior suggestive of lumbar radiculopathy. The finding that glial activation and enhanced IL-1beta expression are observed in the spinal cord after root injury supports a central, neuroimmune component in the generation of lumbar radiculopathy. A further understanding of the immunologic consequences of root injury may lead to further development and the novel use of selective cytokine-inflammatory inhibitors for the treatment of low back pain associated with radiculopathy.
A prospective study of 17,774 patients who consulted spine centers in which the impact of spinal disorders and comorbidities on physical functional status were evaluated.
To quantify the effect ...spinal diagnoses have on patients' physical functional status (SF-36 Physical Component Summary PCS score) compared with other common conditions and to quantify the effects of comorbidities on physical functional status in spine patients.
The burden of spinal conditions on a patient's function and the role that comorbidities play in this affliction are poorly quantified in the literature.
Data from the Health Survey Questionnaire were prospectively gathered through the National Spine Network, a nonprofit consortium of spine-focused practices. Each patient's SF-36 score was summarized into a single PCS score. The correlation between diagnosis and comorbidity and PCS score was assessed using multivariate linear regression.
The study patients were a mean of 47.5 years of age, 54.7% were female, 52.3% had lumbosacral diagnoses, and 82.0% had had 3 or more months of pain. The population had a mean PCS score of 30.4 +/- 9.95 (SD) compared with 50.0 +/- 10.00 for the general United States population. The more comorbidities in a patient, the lower the PCS score (Spearman rank correlation = -0.27). The five comorbid conditions that lowered the PCS the most included congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), renal failure, rheumatoid arthritis, and lupus (all P <0.001). In multiple linear regression analysis, age, gender, diagnosis, and comorbidity explained 12.1% of the variance in PCS score.
The PCS score is greatly affected in patients with spinal problems. The study population's PCS (30.4) was lower or similar to the PCS for patients with other illnesses reported in the literature: CHF (31.0), COPD (33.9), SLE (37.1), cancer (38.4), primary total hip arthroplasty (29.0), primary total knee arthroplasty (32.6), and glenohumeral degenerative joint disease (35.2). Further, the presence of comorbidity in spine patients adds to the burden of spinal conditions on functional status.
In the present study, we report the characterization of the p53 tumor suppressor pathway in the 60 cell lines of the National Cancer Institute (NCI) anticancer drug screen, as well as correlations ...between the integrity of this pathway and the growth-inhibitory potency of 123 anticancer agents in this screen. Assessment of p53 status in these lines was achieved through complete p53 cDNA sequencing, measurement of basal p53 protein levels and functional assessment of (a) transcriptional activity of p53 cDNA from each line in a yeast assay, (b) gamma-ray-induced G1 phase cell cycle arrest, and (c) gamma-ray-induced expression of CIP1/WAF1, GADD45, and MDM2 mRNA. Our investigations revealed that p53 gene mutations were common in the NCI cell screen lines: 39 of 58 cell lines analyzed contained a mutant p53 sequence. cDNA derived from almost all of the mutant p53 cell lines failed to transcriptionally activate a reporter gene in yeast, and the majority of mutant p53 lines studied expressed elevated basal levels of the mutant p53 protein. In contrast to most of the wild-type p53-containing lines, cells containing mutant p53 sequence were also deficient in gamma-ray induction of CIP1/WAF1, GADD45, and MDM2 mRNA and the ability to arrest in G1 following gamma-irradiation. Taken together, these assessments provided indications of the integrity of the p53 pathway in the 60 cell lines of the NCI cell screen. These individual p53 assessments were subsequently used to probe a database of growth-inhibitory potency for 123 "standard agents," which included the majority of clinically approved anticancer drugs. These 123 agents have been tested against these lines on multiple occasions, and a proposed mechanism of drug action had previously been assigned to each agent. Our analysis revealed that cells with mutant p53 sequence tended to exhibit less growth inhibition in this screen than the wild-type p53 cell lines when treated with the majority of clinically used anticancer agents: including DNA cross-linking agents, antimetabolites, and topoisomerase I and II inhibitors. Similar correlations were uncovered when we probed this database using most of the other indices of p53 status we assessed in the lines. Interestingly, a class of agents that differed in this respect was the antimitotic agents. Growth-inhibitory activity of these agents tended, in this assay, to be independent of p53 status. Our characterization of the p53 pathway in the NCI cell screen lines should prove useful to researchers investigating fundamental aspects of p53 biology and pharmacology. This information also allows for the large-scale analysis of the more than 60,000 compounds tested against these lines for novel agents that might exploit defective p53 function as a means of preferential toxicity.
Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together ...with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10
), 3p22.1 (rs67311347, P=2.5 × 10
), 3q26.2 (rs10936602, P=8.8 × 10
), 8p21.3 (rs2241261, P=5.8 × 10
), 10q24.33-q25.1 (rs11813268, P=3.9 × 10
), 11q22.3 (rs74911261, P=2.1 × 10
) and 14q24.2 (rs4903064, P=2.2 × 10
). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
Topoisomerase 1 (top1) inhibitors are proving useful against a range of refractory tumors, and there is considerable interest in the development of additional top1 agents. Despite crystallographic ...studies, the binding site and ligand properties that lead to activity are poorly understood. Here we report a unique approach to quantitative structure-activity relationship (QSAR) analysis based on the National Cancer Institute's (NCI) drug databases. In 1990, the NCI established a drug discovery program in which compounds are tested for their ability to inhibit the growth of 60 different human cancer cell lines in culture. More than 70 000 compounds have been screened, and patterns of activity against the 60 cell lines have been found to encode rich information on mechanisms of drug action and drug resistance. Here, we use hierarchical clustering to define antitumor activity patterns in a data set of 167 tested camptothecins (CPTs) in the NCI drug database. The average pairwise Pearson correlation coefficient between activity patterns for the CPT set was 0.70. Coherence between chemical structures and their activity patterns was observed. QSAR studies were carried out using the mean 50% growth inhibitory concentrations (GI(50)) for 60 cell lines as the dependent variables. Different statistical methods, including stepwise linear regression, principal component regression (PCR), partial least-squares regression (PLS), and fully cross-validated genetic function approximation (GFA) were applied to construct quantitative structure-antitumor relationship models. For our data set, the GFA method performed better in terms of correlation coefficients and cross-validation analysis. A number of molecular descriptors were identified as being correlated with antitumor activity. Included were partial atomic charges and three interatomic distances that define the relative spatial dispositions of three significant atoms (the hydroxyl hydrogen of the E-ring, the lactone carbonyl oxygen of the E-ring, and the carbonyl oxygen of the D-ring). The cross-validated r(2) for the final GFA model was 0.783, indicating a predictive QSAR model.
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